Drugs serve as positive reinforcers to maintain and strengthen behavior leading to their administration. In many situations, drugs of abuse function through pharmacological and behavioral mechanisms to persistently sustain long sequences of drug seeking behavior that are very resistant to extinction. These long sequences of drug-seeking behavior can be analyzed using schedule-controlled performances in the same way as operant behavior maintained by other events such as food or shock. Using a variety of intravenous self-administration procedures in rats and primates, ongoing experiments are being conducted to evaluate behavior maintained by drugs and the ability of pharmacological treatments, (i.e., antagonist administration or the development of dependence) and/or behavioral manipulations to modify drug self-administration behavior and/or food-maintained behavior. These studies compare responding maintained under fixed-ratio, fixed-interval and complex second-order schedules, by various drugs including cocaine, nicotine and other psychomotor stimulants, benzodiazepines and other sedative/anxiolytics, morphine and other opioids and d-9 THC (the active ingredient of marijuana). Studies with nicotine in rodents have produced an inconsistent pattern of results regarding its reinforcing properties. We have shown using the intravenous self-administration paradigm, that nicotine can support responding under a fixed-ratio schedule of reinforcement. Reliable extinction was observed when saline was substituted for nicotine or by pretreatment with the nicotine receptor antagonist mecamylamine. In addition, we have developed an acquisition paradigm that is free from previous food shaping and food deprivation experience, a model that can assess the initiation phase of nicotine-seeking behavior. The Long-Evans strain of rats were found to be less sensitive to nicotine than Sprague-Dawley rats. A regimen consisting of daily injections of nicotine for 7 days was found to facilitate the acquisition of nicotine self-administration. These results strongly suggest that nicotine can serve as a reinforcer in rodents.